Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neutrophils are mobilized to the vascular wall during vessel inflammation. Published data are conflicting on phagocytic nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activation during the hypertensive state, and the capacity of angiotensin II (Ang II) to modulate the intracellular redox status has not been analyzed in neutrophils. We here describe that Ang II highly stimulates endogenous and extracellular O2- production in these cells, consistent with the translocation to the cell membrane of the cytosolic components of NADPH oxidase, p47phox, and p67phox. The Ang II-dependent O2- production was suppressed by specific inhibitors of AT1 receptors, of the p38MAPK and ERK1/2 pathways, and of flavin oxidases. Furthermore, Ang II induced a robust phosphorylation of p38MAPK, ERK1/2, and JNK1/2 (particularly JNK2), which was hindered by inhibitors of NADPH oxidase, tyrosine kinases, and ROS scavengers. Ang II increased cytosolic Ca2+ levels-released mainly from calcium stores-enhanced the synthesis de novo and activity of calcineurin, and stimulated the DNA-binding activity of the transcription factor NF-kappaB in cultured human neutrophils. Present data demonstrate for the first time a stimulatory role of Ang II in the activation of phagocytic cells, underscore the relevant role of ROS as mediators in this process, and uncover a variety of signaling pathways by which Ang II operates in human neutrophils.
...
PMID:Oxidative stress is a critical mediator of the angiotensin II signal in human neutrophils: involvement of mitogen-activated protein kinase, calcineurin, and the transcription factor NF-kappaB. 1266 41

The MAPKs are important transducers of growth and stress stimuli in virtually all eukaryotic cell types. In the mammalian heart, MAPK signaling pathways have been hypothesized to regulate myocyte growth in response to developmental signals or physiologic and pathologic stimuli. Here we generated cardiac-specific transgenic mice expressing dominant-negative mutants of p38alpha, MKK3, or MKK6. Remarkably, attenuation of cardiac p38 activity produced a progressive growth response and myopathy in the heart that correlated with the degree of enzymatic inhibition. Moreover, dominant-negative p38alpha, MKK3, and MKK6 transgenic mice each showed enhanced cardiac hypertrophy following aortic banding, Ang II infusion, isoproterenol infusion, or phenylephrine infusion for 14 days. A mechanism underlying this enhanced-growth profile was suggested by the observation that dominant-negative p38alpha directly augmented nuclear factor of activated T cells (NFAT) transcriptional activity and its nuclear translocation. In vivo, NFAT-dependent luciferase reporter transgenic mice showed enhanced activation in the presence of the dominant-negative p38alpha transgene before and after the onset of cardiac hypertrophy. More significantly, genetic disruption of the calcineurin Abeta gene rescued hypertrophic cardiomyopathy and depressed functional capacity observed in p38-inhibited mice. Collectively, these observations indicate that reduced p38 signaling in the heart promotes myocyte growth through a mechanism involving enhanced calcineurin-NFAT signaling.
...
PMID:Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NFAT signaling. 1275 Mar 97

Connective tissue growth factor (CTGF) is a polypeptide implicated in the extracellular matrix synthesis. Previous studies have provided evidence that angiotensin II (Ang II) promotes collagen synthesis and regulates collagen degradation. We investigated whether or not CTGF mediates the profibrotic effects of Ang II in the heart and kidneys and the role of calcineurin-dependent pathways in CTGF gene regulation. In transgenic rats harboring human renin and angiotensinogen genes, Ang II induced an age-dependent increase in myocardial CTGF expression, which was 3.5-fold greater compared to normotensive Sprague Dawley (SD) rats. CTGF overexpression correlated closely with the Ang II-induced rise in blood pressure. CTGF mRNA and protein were located predominantly in areas with leukocyte infiltration, myocardial, and vascular lesions and co-localized with TGFbeta(1), collagen I, and collagen III mRNA expressions. Ang II induced CTGF mRNA and protein to a lesser extent in the kidneys, predominantly in glomeruli, arterioles, and in the interstitium with ample inflammation. However, no expression was found in the right ventricle or pulmonary arteries. Blockade of calcineurin activity by cyclosporine A completely normalized Ang II-induced CTGF overexpression in heart and kidney, suppressed the inflammatory response, and mitigated Ang II-induced cell proliferation and apoptosis. In contrast, blockade of mTOR (target of rapamycin) pathway by everolimus, further increased the expression of CTGF even though everolimus ameliorated cell proliferation and T-cell-mediated inflammation. Our findings provide evidence that CTGF mediates Ang II-induced fibrosis in the heart and kidneys via blood pressure and calcineurin-dependent pathways.
...
PMID:Angiotensin II induces connective tissue growth factor gene expression via calcineurin-dependent pathways. 1281 40

Angiotensin II and extracellular potassium stimulate aldosterone production in adrenal glomerulosa cells by mobilizing the calcium messenger system. This response requires calcium influx across the plasma membrane, followed by calcium uptake into the mitochondria. It has been proposed that calcium is transported to the mitochondria via the lumen of the endoplasmic reticulum, acting as a kind of intracellular calcium pipeline. This hypothesis has been tested in the present study by measuring intramitochondrial calcium variations in H295R cells with a new fluorescent calcium probe, ratiometric pericam. Calyculin A, a protein phosphatase inhibitor, induced the formation of a large cortical layer of actin filaments, removing the peripheral endoplasmic reticulum away from the plasma membrane and thereby physically uncoupling the calcium channels from the pipeline. The mitochondrial calcium response to potassium was markedly reduced after calyculin treatment, but that of AngII was unaffected. Under the same conditions, potassium-stimulated pregnenolone and aldosterone production was significantly reduced, whereas the steroidogenic response to AngII remained unchanged. The inhibitory action of calyculin A on the responses to potassium was not mediated by a modification of the calcium channel activity and was not accompanied by a reduction of the cytosolic calcium response. It therefore appears that, in H295R cells, the organization of the actin cytoskeleton at the cell periphery influences the steroidogenic action of potassium, but not the response to angiotensin II. The response to potassium is proposed to be dependent on the endoplasmic reticulum-mediated transfer of calcium entering through plasma membrane calcium channels to the mitochondria.
...
PMID:Intracellular transport of calcium from plasma membrane to mitochondria in adrenal H295R cells: implication for steroidogenesis. 1296 50

Although the role of the calcineurin-dependent pathway in the development of cardiac hypertrophy has been intensively studied, little is known of its role in vascular inflammatory diseases such as atherosclerosis and restenosis after angioplasty. To help elucidate the role of calcineurin in vascular inflammation, we infected cultured vascular smooth muscle cells (VSMCs) with an adenovirus construct expressing a constitutively active mutant of calcineurin, and examined its effect on the expression of monocyte chemoattractant protein-1 (MCP-1). We also examined the role of calcineurin in vivo using a transluminal wire injury model of the rat femoral artery. Forced activation of calcineurin significantly increased the expression of MCP-1 both at the transcriptional and protein levels. Angiotensin II (Ang II) also significantly stimulated MCP-1 expression, and this increase was significantly inhibited by cyclosporin A (CyA). Constitutive activation of calcineurin stabilized MCP-1 mRNA without enhancing MCP-1 promoter activity. In accordance with the results, Ang II-induced increase of MCP-1 promoter activity was not suppressed by CyA. Ang II stabilized MCP-1 mRNA, and this effect of Ang II was diminished by CyA. CyA suppressed MCP-1 expression in the femoral artery after the transluminal mechanical injury. CyA also inhibited macrophage infiltration and neointimal formation in the wire-injured femoral arteries. These results suggested that calcineurin mediates vascular inflammation via stimulation of MCP-1 expression in VSMCs and macrophage infiltration.
...
PMID:Calcineurin promotes the expression of monocyte chemoattractant protein-1 in vascular myocytes and mediates vascular inflammation. 1473 59

The main regulators of aldosterone secretion in adrenal gland zona glomerulosa (ZG) cells are the hormones angiotensin II (Ang II) and adrenocorticotrophin (ACTH) and small increases in the extracellular potassium (K(+)) concentration. The action of these agonists is mediated by different signalling systems - ACTH is mediated by cAMP and activation of protein kinase A while Ang II and K(+) activate two protein kinases, Ca(2+)-calmodulin-dependent protein kinase (CamK) and diacylglycerol-dependent protein kinase (PKC). Ang II, besides being one of the main agonists for the secretion of aldosterone, also stimulates proliferation of ZG cells, a process mediated by mitogen-activated protein kinases (MAPKs). Recent studies aimed at elucidating the molecular mechanisms underlying cell proliferation have shown that calcineurin is the principal regulator of MAPKs activity. The purpose of this review is to discuss experimental evidence of possible reciprocal influences between the signalling pathways regulating proliferation and steroidogenesis in ZG cells.
...
PMID:Reciprocal influences between the signalling pathways regulating proliferation and steroidogenesis in adrenal glomerulosa cells. 1517 20

Voltage-gated K+ (Kv) channels control the excitability of arterial smooth muscle. However, the molecular mechanisms regulating Kv channel function in smooth muscle remain unclear. We examined the hypothesis that the vasoactive peptide angiotensin II (Ang II) regulates arterial smooth muscle Kv channel function via calcineurin-dependent activation of the transcription factor NFAT. We found that sustained administration of Ang II decreased Kv currents (IKv) by reducing the expression of Kv2.1 K+ channel subunits. This effect of Ang II was independent of pressure but required Ca2+ influx through L-type Ca2+ channels. Consistent with our hypothesis, we found that calcineurin and NFATc3 are obligatory components of the signaling cascade mediating reduced IKv by Ang II. We conclude that sustained Ang II exposure increases smooth muscle Ca2+, which leads to activation of calcineurin and NFATc3, culminating in decreased Kv2.1 expression and reduced IKv function. These results support the novel concept that NFATc3 controls the excitability of arterial smooth muscle by regulating Kv2.1 expression.
...
PMID:NFATc3 regulates Kv2.1 expression in arterial smooth muscle. 1532 14

Angiotensin II (Ang II) plays a central role in cardiovascular physiology and disease. Ang II type I receptor (AT1) is thought to mediate most actions of Ang II. A novel AT1 receptor intracellular partner called AT1 receptor-associated protein (ATRAP) was identified, but its exact function has not been elucidated. A yeast two-hybrid screen using ATRAP as bait identified calcium-modulating cyclophilin ligand (CAML) as an ATRAP partner. Yeast two-hybrid and coimmunoprecipitation analysis demonstrated that the N-terminal hydrophilic domain of CAML (amino acids (aa) 1-189) mediates a specific interaction between ATRAP and CAML. Our analysis also showed that aa 40-82 of ATRAP contribute to this interaction. Bioluminescence resonance energy transfer and intracellular colocalization analysis by immunofluorescence in HEK293 cells verified this association within endoplasmic reticulum vesicular structures. Functionally, transcriptional reporter assays and RNA interference ATRAP experiments demonstrated that ATRAP knockdown increased nuclear factor of activated T cells (NFAT) activity. Overexpression of ATRAP decreased Ang II- or CAML-induced NFAT transcriptional activation, whereas an ATRAP-interacting domain of CAML (aa 1-189) sensitized NFAT activation in response to Ang II. These results indicate that CAML is an important signal transducer for the actions of Ang II in regulating the calcineurin-NFAT pathway and suggest that the interaction of CAML with ATRAP may mediate the Ang II actions in vascular physiology.
...
PMID:Identification of calcium-modulating cyclophilin ligand (CAML) as transducer of angiotensin II-mediated nuclear factor of activated T cells (NFAT) activation. 1566 45

1 The calcineurin (CaN) enzyme-transcriptional pathway is critically involved in hypertrophy of heart muscle in some animal models. Currently there is no information concerning the regulation of CaN activation by endogenous agonists in human heart. 2 Human right ventricular trabeculae from explanted human (14 male/2 female) failing hearts were set up in a tissue bath and electrically paced at 1 Hz and incubated with or without 100 nM endothelin-1 (ET-1), 10 M, angiotensin-II (Ang II) or 20 nM human urotensin-II (hUII) for 30 min. Tissues from four patients were incubated with 200 nM tacrolimus (FK506) for 30 min and then incubated in the presence or absence of ET-1 for a further 30 min. 3 ET-1 increased contractile force in all 13 patients (P<0.001). Ang II and hUII increased contractile force in three out of eight and four out of 10 patients but overall nonsignificantly (P>0.1). FK506 had no effect on contractile force (P=0.12). 4 ET-1, Ang II and hUII increased calcineurin activity by 32, 71 and 15%, respectively, while FK506 reduced activity by 34%. ET-1 in the presence of FK506 did not restore calcineurin activity (P=0.1). 5 There was no relationship between basal CaN activity and expression levels in the right ventricle. Increased levels of free phosphate were detected in ventricular homogenates that were incubated with PKC(epsilon) compared to samples incubated without PKC(epsilon). 6 Endogenous cardiostimulants which activate G(alpha)q-coupled receptors increase the activity of calcineurin in human heart following acute (30 min) exposure. PKC may contribute to this effect by increasing levels of phosphorylated calcineurin substrate.
...
PMID:Activation of calcineurin in human failing heart ventricle by endothelin-1, angiotensin II and urotensin II. 1582 52

Transient receptor potential (TRP) proteins have been identified as cation channels that are activated by agonist-receptor coupling and mediate various cellular functions. TRPC7, a homologue of TRP channels, has been shown to act as a Ca2+ channel activated by G protein-coupled stimulation and to be abundantly expressed in the heart with an as-yet-unknown function. We studied the role of TRPC7 in G protein-activated signaling in HEK293 cells and cultured cardiomyocytes in vitro transfected with FLAG-tagged TRPC7 cDNA and in Dahl salt-sensitive rats with heart failure in vivo. TRPC7-transfected HEK293 cells showed an augmentation of carbachol-induced intracellular Ca2+ transient, which was attenuated under a Ca2+-free condition or in the presence of SK&F96365 (a Ca2+-permeable channel blocker). Upon stimulation with angiotensin II (Ang II), cultured neonatal rat cardiomyocytes transfected with TRPC7 exhibited a significant increase in apoptosis detected by TUNEL staining, accompanied with a decrease in the expression of atrial natriuretic factor and destruction of actin fibers, as compared with non-transfected cardiomyocytes. Ang II-induced apoptosis was inhibited by CV-11974 (Candesartan; Ang II type 1 [AT1] receptor blocker), SK&F96365, and FK506 (calcineurin inhibitor). In Dahl salt-sensitive rats, apoptosis and TRPC7 expression were increased in the failing myocardium, and a long-term treatment with temocapril, an angiotensin-converting enzyme inhibitor, suppressed both. Our findings suggest that TRPC7 could act as a Ca2+ channel activated by AT1 receptors, leading to myocardial apoptosis possibly via a calcineurin-dependent pathway. TRPC7 might be a key initiator linking AT1-activation to myocardial apoptosis, and thereby contributing to the process of heart failure.
...
PMID:Transient receptor potential (TRP) protein 7 acts as a G protein-activated Ca2+ channel mediating angiotensin II-induced myocardial apoptosis. 1683 6


<< Previous 1 2 3 4 5 6 7 8 Next >>

---